ES2223113T3 - COSMETIC COMPOSITION USEFULLY FOR SKIN WHITENING AND INHIBITING AGENT OF MELANOGENESIS THAT INCLUDES SUCH A COSMETIC COMPOSITION. - Google Patents

Abstract

COSMETIC COMPOSITION USEFULLY PARTICULAR FOR SKIN WHITENING, CHARACTERIZED BECAUSE IT CONTAINS, IN ASSOCIATION WITH ANY APPROPRIATE EXCIPIENT, AT LEAST A COMPOSITE OF GENERAL FORMULA (I) IN WHICH: R 1 REPRESENTS A HYDROGEN HYDROGEN GROUP, A GROUP OR A TIAZOLINA GROUP, R 2 REPRESENTS A HYDROGEN ATOM, A LINEAR OR RAMIFIED RENTAL GROUP OR A LINEAR OR RAMIFIED RENT GROUP REPLACED BY A CARBOXYL, HYDROXYL, AMINA OR TIOL GROUP, R 3 REPRESENTS A HYDROGEN ATOMO, A GRID OR RAMIFIED, AN ARIALQUILO GROUP, AN ACILO GROUP OR AN ACILOXI GROUP, R 4 REPRESENTS A HYDROGEN ATOM OR A RENTED GROUP OR A HYDROXYL GROUP OR A LINEAR OR RAMIFIED RENTING GROUP.

Description

Cosmetic composition especially useful for skin bleaching and melanogenesis inhibitory agent that It includes such a cosmetic composition.

The present invention aims at a cosmetic composition especially useful for bleaching the skin, which includes a compound of general formula (I) described more below, in association with any appropriate excipient; the present The object of the invention is also an agent that inhibits melanogenesis that includes such a cosmetic composition.

The compounds (I) according to the invention are of following general formula:

\melm{\delm{\para}{\hskip-0,3cm
HNR _{3} }}{C}{\uelm{\para}{R _{1} }}

----

\melm{\delm{\para}{R _{5} }}{P}{\uelm{\dpara}{O}}

---- OR_{4}(I) R_ {2} ----

 \ melm {\ delm {\ para} {\ hskip-0,3cm
HNR3}} {C} {\ uelm {\ para} {R1}} 

----

 \ melm {\ delm {\ para} {R5}} {P} {\ uelm {\ dpara} {O}} 

---- OR_ {4}

in the which:

R1 represents a hydrogen atom, a (C 1 -C 4) group linear or branched alkyl or a thiazoline group,

R 2, R 3 and R 4 each represent a hydrogen atom,

R 5 represents a hydrogen atom or a hydroxyl group.

For many years, it is checked in cosmetics a growing interest for depigmenting products: age spots (senile lentigo), cloth (chloasma), freckles, pigmentation spots that appear on mature skin after from prolonged exposure to the sun, they are poorly supported by those who They suffer. Fashion phenomena favoring clear skins in Asia and in Africa, also represent targeted factors for Promote the birth of depigmenting products.

Melanin is a pigment synthesized by melanocytes, specialized cells located at the layer level Basal of the epidermis. Hyperpigmentation is often due to a melanocytic hyperactivity, possibly accompanied by a increased number of melanocytes.

Within the melanocytes, the reactions of oxidation that lead to the formation of melanin, are mainly catalyzed by tyrosinase. Pigments formed are distributed evenly on the surface of the epidermis, except when the mechanism is disturbed: melanin is then accumulates anarchically on certain sites.

The depigmenting properties of certain substances have been known for a long time: since 1936, Oettel observed the decrease in pigmentation of the hair of black cats to which hydroquinone has been administered (Hemsworth BN, J. Soc. Cosmet. Chem, 1973, 24 , 727-733).

A certain number of substances have shown a depigmenting activity, but some cannot be used in cosmetic due to its toxicity (for example the salts of mercury), to the skin irritation they cause (mercaptoamines, oxidizing products such as hydrogen peroxide) or the fact of the excessive slowness of its action (ascorbic acid or derivatives of ascorbic acids).

Other compounds such as derivatives phenolics, corticosteroids, vitamin A analogues, certain plant extracts are included in the composition of numerous depigmenting preparations currently marketed

However, these compounds have a certain number of inconveniences within the phenolic derivatives, the hydroquinone, tyrosinase inhibitor, causes a non number negligible side reactions (inflammatory reactions, burns, itching, irreversible spot dyschromia); the corticosteroids also generate such secondary manifestations which are unusable in cosmetics; Vitamin A analogues (beta carotene, cantaxanthin) are able to block activity melanocytic but the problem posed by these substances is get a penetration into cells without being metabolized by cellular enzymes.

Vegetable extracts, which contain, be arbutin (glucose hydroquinone), either flavonoids, or derivatives cinnamic, they are also used as depigmenting agents but they have A very slow action.

In general, the problem of these depigmenting agents from the prior art is that two minimum months of treatment are necessary to see the appearance of the first results in vivo .

To especially remedy these inconveniences, but also uncheck the compositions bleaches based on aminophosphonic derivatives, objects of summaries of documents JP 08333235 and JP 61069707, an objective of the present invention is to propose the use, for skin bleaching, of compounds whose structure and process Preparation are known, but they have an activity Amazing for skin whitening.

An objective of the present invention is to propose a cosmetic composition useful particularly for the skin bleaching, characterized in what it contains, in association with any appropriate excipient, at least one compound of general formula (I):

\melm{\delm{\para}{\hskip-0,3cm
HNR _{3} }}{C}{\uelm{\para}{R _{1} }}

----

\melm{\delm{\para}{R _{5} }}{P}{\uelm{\dpara}{O}}

---- OR_{4}(I) R_ {2} ----

 \ melm {\ delm {\ para} {\ hskip-0,3cm
HNR3}} {C} {\ uelm {\ para} {R1}} 

----

 \ melm {\ delm {\ para} {R5}} {P} {\ uelm {\ dpara} {O}} 

---- OR_ {4}

in the which:

R1 represents a hydrogen atom, a (C 1 -C 4) group linear or branched alkyl or a thiazoline group,

R 2, R 3, R 4 each represent a hydrogen atom,

R 5 represents a hydrogen atom or a hydroxyl group.

Advantageously, the compound of formula (I) is just as R_ {1} represents a group (C 1 -C 4) alkyl, R 2 and R 3 each represents a hydrogen atom and R 5 represents a hydrogen atom

Following a preferred embodiment of the invention, the compound of formula (I) is the acid 1-amino-ethylphosphin.

According to another preferred embodiment of the invention, the compound of formula (I) is the acid 1-amino-3-methylbutylphosphin.

Preferably, the cosmetic composition according to The invention includes, in addition to the compound (s) of the formula general (I), anti-inflammatory, other bleaching agents of the skin, and / or antioxidants.

Advantageously, the compound content of general formula (I) is between 0.1 and 20% by weight with respect to total weight of the composition and preferably between 0.5 and 5% in weight with respect to the total weight of the composition.

According to a special embodiment, the composition according to the invention further includes a compound organo-silicic of general formula (II) next:

\melm{\delm{\para}{R _{8} }}{S}{\uelm{\para}{R _{6} }}

i --- R_{9}(II) R7 {---}

 \ melm {\ delm {\ para} {R 8}} {S} {\ uelm {\ para} {R 6}} 

i --- R_ {9}

in which at least one of the radicals R 6, R 7, R 8 or R 9 represents a group, hydroxyl, alkoxy, acyloxy, aryloxy or amino or a halogen atom and at least one other of said radicals R 6, R 7, R_ {8} or R_ {9} is a group I rent.

Following a special embodiment of the invention, the cosmetic composition further includes a pseudodipeptide of the type obtained by reaction between Histamine and an amino acid.

Preferably, this pseudodipeptide is the β-alanyl-histamine.

Preferably, the excipient used in the cosmetic composition according to the invention, is a micro dispersion without tense-active.

Advantageously, the cosmetic composition according to the invention is presented in the form of liposomes, of micro particles or nano particles.

Following an advantageous variant of the invention, The cosmetic composition according to the invention is presented under the form of a cream, a milk, a lotion, or a gel.

A further object of the invention is to propose a melanogenesis inhibitor, characterized in that It includes a cosmetic composition as described above.

The present invention is illustrated not limited by the detailed description and examples that follow.

The compounds of general formula (I) are commercially available and can be prepared according to the methods described in the prior art, and particularly following the protocol described in J. Chem.Soc.Perkin.trans.I, 1984 by BAYLIS and to the.

Preferred compounds of formula (I) are those for which R1 represents a hydrogen atom, a group (C 1 -C 4) linear alkyl or branched or a thiazoline group, R 2 R 3 and R 4 each represents a hydrogen atom, and R 5 represents a hydrogen atom or a hydroxyl group.

Within these compounds, acids aminophosphines, i.e. the compounds of formula (I) in which R 5 represents a hydrogen atom, they are more especially preferred.

The compounds according to the invention are acidic. α-amino phosphonic or α-amino phosphine and thus have a structure very close to that of an α-amino natural acid

The compounds included in the compositions according to the invention they also have an inhibitory action on the melanogenesis The mechanisms of this action are not exactly known, and it is possible that the proven activity results from numerous mechanisms that act simultaneously and possibly of synergistic way.

Thus, the compounds according to the invention can used for skin whitening because they are inhibitors of  tyrosinase, and / or because they act at other levels.

According to an advantageous embodiment of the In the cosmetic compositions according to the invention, add at least one other to the compound of general formula (I) compound useful for skin bleaching. Advantageously, the (the) said other compound (s) useful (s) for skin whitening include at least one tyrosinase inhibitor compound.

Preferably, the said (s) other compound (s) useful for bleaching of the skin are ascorbic acid and / or its derivatives particularly its stearate or palmitate salts or ascorbic acid conjugated to a stabilizer, such as particularly a compound  marketed under the brand name ASCORBOSILANE C by the applicant.

The said (s) other (s) compound (s) useful for skin bleaching they can also be kojic acid or its derivatives.

According to an advantageous embodiment of the invention, the said other compound (s) useful for skin bleaching may also be natural plant extracts, and more especially the plant extract. White mulberry ( Morus alba ), green tea ( Théa sinensis ), the matricaria ( Chamomilla recutica ). Green tea is known for its properties as an inhibitor of the transport of mature melanocytes to keratinocytes. It is also a tyrosinase inhibitor product. The matricaria is an antagonistic endothelium, which inhibits melanogenesis induced by UV rays

According to another special mode of realization of the invention, is added in cosmetic compositions according to the invention at least one anti inflammatory, particularly soothing. Advantageously, this anti inflammatory is of natural origin. Preferably, it is a licorice phytosterol.

It is known for example that some dyschromias, Like age spots, they appear with age. The inventors have observed that fighting against aging, particularly thanks to anti-aging cosmetic compositions, the skin manifestations due to age and particularly prevents the appearance of age spots.

Thus, with respect to a first embodiment Special invention is associated with a known cosmetic asset by its anti-aging action to a compound of general formula (I).

Preferably, the cosmetic asset anti-aging is a silicic organ compound biologically active, of the type of commercialized silanoles by the Applicant.

Advantageously, this silicon derivative Organic responds to the following general formula (II):

\melm{\delm{\para}{R _{8} }}{S}{\uelm{\para}{R _{6} }}

i --- R_{9}(II) R7 {---}

 \ melm {\ delm {\ para} {R 8}} {S} {\ uelm {\ para} {R 6}} 

i --- R_ {9}

in the which

at least one of the radicals R 6, R 7, R 8, R 8 represents a hydroxyl group or a hydrolysable group including at least one oxygen atom such that there is an Si-O link, and at least one of the other said radicals R 6, R 7, R 8, R 9 is a group I rent.

In addition, it has been proven that the phenomena of glycation, lipid peroxidation or situations of oxidative stresses can result in doing appear excessive pigmentation at the skin level. Is for example shown that the synthesis of lipofuscin type compounds, polymer of aldehyde derivatives known to be a pigment due to age, it is regulated by reactions of pro and anti- oxidation.

That is why, according to one embodiment in particular, that the cosmetic compositions according to the invention are performed by associating at least one compound of general formula (I) with  At least one antioxidant

In addition, it is now known that DNA destruction and / or repair induces melanization.

According to a second embodiment of the invention, the cosmetic compositions according to the invention include, in addition to the compound of formula (I) and possibly, but not necessarily, a silicon derivative organic, a compound known particularly for its properties protective and / or repairing DNA.

Preferably, this compound with properties DNA protectors are a pseudodipeptide of those type obtained by reaction between histamine and an amino acid and described in international patent application WO94 / 19325. Preferably, this pseudodipeptide is the β-alanyl-histamine, likewise known for its antioxidant properties and for its ability to reduce hydroperoxides of fatty acids.

The proportions of compound of general formula (I) in the compositions according to the invention are a function of the ingredients included in these compositions, and may vary from 0.1% to 20% by weight. However, preferred proportions vary. between 0.5% and 5% by weight.

In all cosmetic compositions according to invention, the excipient can all be cosmetically excipient acceptable. Advantageously, the excipient is a microdispersion without tense-active.

According to, a particular embodiment of the invention, the cosmetic compositions according to the invention are present in the form of liposomes or micro particles or of nanoparticles.

The cosmetic compositions according to the invention they can also be presented in any form cosmetically appropriate, and particularly in all appropriate forms with topical use, such as cream, milk, of lotion or gel.

The object of the invention is also an agent melanogenesis inhibitor that includes one of the compositions Cosmetics previously described.

The melanin inhibitory activity of compounds of formula (I) included in the compositions according to the invention is illustrated not limitingly by the examples that follow:

Example 1

In vitro , the melanin inhibitory activity of the following 1-amino-ethylphosphinic acid of formula developed (Ia) is tested:

one

The reference used is ascorbic acid in solution at 0, 3. 10-3 mol. 1 -1.

2 ml of solution are mixed L-DOPA, with 1.25 ml of tyrosinase (2500 Units / ml) and with 2 ml of the product (Ia) in solution at 1 10-3 mol. 1 <-1> is then completed with 20 ml of buffer phosphate (NaH 2 PO 4 at 0.1 mol. 1 -1 + Na 2 HPO 4 to 0.1 mol. 1 -1, pH 6.8). Leave 4 hours at 37 ° C low agitation, and then, a night at room temperature without light. Be add 1 ml of concentrated hydrochloric acid, centrifuge 5 min at 4000 laps / minute. The solid is rinsed with 10 ml of water distilled, centrifuged a second time. It is refluxed of the solid in concentrated acid HC1 6N for 48 hours.

The dried solid is dissolved in 10 ml of toluene, with ultra sounds for 2 minutes, then leave 2 hours at 37 ° C and another  once undergoes the ultra sounds 5 mn. Optical density is measured at 400 nm.

The percentage of melanin inhibition by the 1-amino-ethylphosphinic acid is from 46%

Example 2

In vitro , the melanin inhibitory activity of the following 1-amino-3-methylbutylphosphinic acid of formula (Ib) is tested:

2

applying the example protocol one.

The percentage of melanin inhibition by the 1-amino-3-methylbutylphosphin  It is 44%.

Example 3

The inhibitory activity of the melanin acid 1-amino-ethylphosphine (Ia), in S91 melanoma cell cultures.

The study model used has been developed by Gilchrest (1987). The cells put in cultures they come from a melanoma of Cloudman and respond, like melanocytes normal, at a stimulation U.V. due to increased melanogenesis. The evaluation of melanogenesis is done through the dosage of melanin and the search for the activity of enzymes involved in this metabolism: tyrosinase and dopa-tautomerase. S91 cells are seeded at 2 10 5 cells in boxes of 60 mm diameter and are maintained in an environment of Eagle modified by Dulbecco and supplemented with 10% fetal calf serum.

When the cells reach 50% confluence, The cells are irradiated. The irradiation is 10 mJ / cm2 with  a wavelength of 285 ± 5 nm. During irradiation, the medium is replaced by a solution of saline phosphate (PBS) to Eliminate the formation of toxic derivatives. Immediately after of irradiation the PBS is replaced by a fresh medium supplemented with 7% fetal calf serum with or without the active. After 16 hours of incubation, the medium is removed and replace with a normal medium with or without active. The evaluation of Effect is done 24 and 48 hours after irradiation. The reference of non-irradiated culture is handled in the same way, but in the Darkness during irradiation. Then, the Melanin: Melanocytes are trypsinized, cleaned twice with PBS and solubilized in 0.8 ml of 1N NaOH, under vigorous stirring to the vortex for 10-15 mn and heating to a temperature of 60-80 ° C. The concentration of the Melanin is determined with the OD measurement at 475 nm.

The reference, that is kojic acid, is used in a concentration of 3.3.10 -3 mol. 1 <-1>, and a this concentration, the melanin rate decreases in the cells of 45.2%

The compound (Ia) with a concentration of 0.5.10 <-1> mol.l <-1>, that is much smaller than that of the reference, decreases the rate of melanin in the cells of 47.2%

Example 4 Micro dispersion oil in water without tense-active

Polyisobutene hydrogenated 10.75 g oil mineral 3.00 g heptanoate stearyl 7.25 g parahydroxybenzoate sodium methyl 0.20 g parahydroxybenzoate propyl 0.10 g Acid 1-amino-ethylphosphophinic 1.00 g ALISTIN 0.20 g Carbomer 0.50 g Water 79.00 g

Example 5 Gel

Carbomer 0.70 g sodium methyl parahydroxybenzoate 0.20 g propyl parahydroxybenzoate 0.10 g Acid 1-amino-ethylphosphin 2.00 g Mulberry Extract 3.00 g Water 94.00 g

Example 6 Cream

polyacrylamide C_ {13-14} isoparaffin 2.00 g Laureth 7 imidazolidinyl urea 0.30 g sodium methyl parahydroxybenzoate 0.10 g propyl parahydroxybenzoate 0.05 g Acid 1-amino-ethylphosphin 3.00 g glyceril stearate steareth-25 10.00 g ceteth-20 alcohol stearic Cetearyl octanoate 10.00 g macadamia oil 10.00 g dimethicone 0.2 g dimethicone copolyol 0.3 g glycerin 3.00 g Water csp 100.00 g

Claims (14)

1. Cosmetic composition useful especially for skin bleaching, characterized in that it contains, in association with any appropriate excipient at least one compound of general formula (I): (I) R_ {2} ----

 \ melm {\ delm {\ para} {\ hskip-0,3cm
HNR3}} {C} {\ uelm {\ para} {R1}} 

----

 \ melm {\ delm {\ para} {R5}} {P} {\ uelm {\ dpara} {O}} 

---- OR_ {4} in the which: R1 represents a hydrogen atom, a (C 1 -C 4) group linear or branched alkyl or a thiazoline group, R 2, R 3 and R 4 each represent a hydrogen atom, R 5 represents a hydrogen atom or a hydroxyl group. 2. Cosmetic composition according to claim 1, characterized in that said compound of formula (I) is such as R 1 represents a group (C 1 -C 4) alkyl, R 2 and R_ {3} each represent a hydrogen atom, and R5 represents a hydrogen atom. 3. Cosmetic composition according to any of claims 1 to 2, characterized in that said compound of formula (I) is 1-amino-ethylphosphinic acid. 4. Cosmetic composition according to any of claims 1 to 2, characterized in that said compound of formula (I) is 1-amino-3-methylbutylphosphinic acid. 5. Cosmetic composition according to any one of claims 1 to 4, characterized in that it includes, in addition to anti-inflammatories, other skin bleaching agents, and / or antioxidants. 6. Cosmetic composition according to any one of claims 1 to 5, characterized in that the content of compound of general formula (I) is between 0.1 and 20% by weight with respect to the total weight of the composition. 7. Cosmetic composition according to claim 6, characterized in that the compound content of the general formula (I) is between 0.5 and 5% by weight with respect to the total weight of the composition. 8. Cosmetic composition according to any of claims 1 to 7, characterized in that it further includes an organic silicon derivative of the following general formula (II): (II) R7 {---}

 \ melm {\ delm {\ para} {R 8}} {S} {\ uelm {\ para} {R 6}} 

i --- R_ {9} in which at least one of the radicals R 6, R 7, R 8 or R 9 represents a group hydroxyl, alkoxy, acyloxy, aryloxy, or amino or a halogen atom and at least one other of said radicals R 6, R 7, R 8 or R_ {9} is a group I rent. 9. Cosmetic composition according to any of claims 1 to 8, characterized in that it further includes a pseudodipeptide of the type obtained by reaction between histamine and an amino acid. 10. Cosmetic composition according to claim 9, characterized in that said pseudodipeptide is the
β-alanyl-histamine. 11. Cosmetic composition according to any of claims 1 to 10, characterized in that said excipient is a micro-dispersion without tenside-active. 12. Cosmetic composition according to any of claims 1 to 10, characterized in that it is presented in the form of liposomes, micro particles or nano particles. 13. Cosmetic composition according to any of claims 1 to 12, characterized in that it is presented in the form of a cream, a milk, a lotion, or a gel. 14. Melanogenesis inhibitor agent characterized in that it includes a cosmetic composition according to any of claims 1 to 13.